Detection of intestinal pathogens through host surveillance of bacterial toxins

通过宿主细菌毒素监测来检测肠道病原体

• 批准号: 10321888
• 负责人: Samantha Tse
• 金额: $ 3.17万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10321888
• 关键词: Animal Model; Anti-Infective Agents; Anti-Inflammatory Agents; Bacteria; Bacterial Toxins; Bone Marrow Transplantation; Caenorhabditis elegans; Cells; Cessation of life; Communities; Data; Detection; Development; Embryonic Development; Epithelial Cells; Family; Genes; Genetic Transcription; HNF4A gene; Health; Homologous Gene; Human; Immune; Immune response; Immunocompromised Host; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune Response; Intestines; Lead; Ligands; Metabolism; Modeling; Molecular; Monitor; Natural Immunity; Nuclear Hormone Receptors; Nuclear Receptors; Organism; Oxidation-Reduction; Pathogen detection; Pathogenesis; Pathogenicity; Patients; Pattern; Pattern recognition receptor; Phenazines; Physiological; Positioning Attribute; Process; Protein Isoforms; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Research; Role; Sepsis; Septicemia; Testing; Therapeutic; Toxin; Transcriptional Activation; Transplant Recipients; Virulence; alpha Toxin; chemotherapy; commensal bacteria; commensal microbes; enteric infection; enteric pathogen; gut colonization; gut inflammation; gut microbiome; human pathogen; immune activation; immunoregulation; insight; interest; intestinal epithelium; mutant; novel; pathogen; pathogenic bacteria; pathogenic microbe; programs; response; therapeutic target; transcription factor

PROJECT SUMMARY/ABSTRACT Although commensal and pathogenic bacteria can be recognized by host pattern recognition receptors, intestinal epithelial cells target protective inflammatory responses towards pathogenic organisms through mechanisms that are incompletely understood. Additional mechanisms of pathogen sensing must exist that allow intestinal cells to target inflammatory defenses towards bona fide pathogens during an infection, and not harmless commensal bacteria. Pathogenic bacteria can express virulence determinants. Phenazine toxins are a family of redox active virulence determinants that are produced by a variety of human pathogens, including P. aeruginosa. P. aeruginosa can colonize the intestines of immunocompromised patients and cause fulminant septicemia and subsequent death. The mechanism by which intestinal epithelial cells detect P. aeruginosa, and whether this involves the surveillance of phenazine toxins, is not known. Nuclear hormone receptors (NHR) are transcription factors that program adaptive host responses following recognition of specific exogenous or endogenous ligands. In particular, HNF4⍺ is an NHR expressed in the intestine. In the model organism C. elegans, the HNF4⍺ homolog NHR-86 is required for the transcriptional activation of innate immune effector genes that protect against P. aeruginosa infection. The central hypothesis of this proposal is that intestinal epithelial cells detect infection through the surveillance of pathogen-derived phenazine toxins by NHR-86/ HNF4⍺, which directly activates protective anti-pathogen defenses in the intestinal epithelium. The following key preliminary findings support this central hypothesis: i) P. aeruginosa mutants that cannot make phenazine toxins do not activate C. elegans innate immune defenses; ii) synthetic phenazine toxins can activate immune genes; and iii) induction of immune genes by phenazine toxins is dependent on the expression of NHR-86/ HNF4⍺. In this proposal, Aim 1 will characterize the C. elegans immune response towards bacterial phenazine toxins, and Aim 2 will define the role of intestinal NHR-86/HNF4⍺ in detecting P. aeruginosa infection in C. elegans. The research proposed here will define a new concept of immune activation in intestinal epithelial cells and will also attribute a novel role for NHRs in pathogen sensing in the intestine. Insights from these findings may identify unexplored approaches for the development of anti-inflammatory and anti-infective therapies.

项目总结/摘要 虽然寄生菌和病原菌可以被宿主模式识别受体识别， 肠上皮细胞通过以下途径靶向针对病原体的保护性炎症反应： 不完全理解的机制。必须存在病原体感知的其他机制， 允许肠道细胞在感染期间针对真正的病原体进行炎症防御， 无害的肠道细菌病原菌可以表达毒力决定因子。吩嗪毒素是 一个氧化还原活性毒力决定簇家族，由多种人类病原体产生，包括P. 铜绿。铜绿假单胞菌可在免疫功能低下患者的肠道定植， 败血症和随后的死亡。肠上皮细胞检测铜绿假单胞菌的机制， 这是否涉及监测吩嗪毒素，尚不清楚。核激素受体（NHR） 转录因子，其在识别特异性外源性或外源性受体后编程适应性宿主反应。 内源性配体。特别地，HNF 4 β是在肠中表达的NHR。在模式生物C. 在线虫中，HNF 4的同源物NHR-86是先天性免疫效应子转录激活所必需的。 保护免受铜绿假单胞菌感染的基因这一提议的核心假设是， 上皮细胞通过NHR-86监测病原体衍生的吩嗪毒素来检测感染。 HNF 4 β，直接激活肠上皮细胞的保护性抗病原体防御。以下 关键的初步研究结果支持了这一中心假设：i）不能产生吩嗪的铜绿假单胞菌突变体 毒素不能激活C。elegans先天免疫防御; ii）合成吩嗪毒素可以激活免疫 iii）吩嗪毒素对免疫基因的诱导依赖于NHR-86/NHR-88基因的表达。 HNF 4在这个建议中，目标1将描述C。线虫对细菌吩嗪的免疫反应 目的2将确定肠NHR-86/HNF 4酶在检测铜绿假单胞菌感染中的作用。 优美的本文提出的研究将定义肠上皮细胞免疫激活的新概念 细胞，也将归因于一个新的作用，NHRs在肠道病原体传感。从这些见解 这些发现可能会发现开发抗炎和抗感染药物的未探索的方法， 治疗